All references cited herein are hereby incorporated in their entirety by reference.
Bovine respiratory disease (BRD) occurs in both dairy and beef cattle and is one of the leading causes of economic loss to the cattle industry throughout the world. These economic losses are due to excessive mortality, reduced weight gains as well as treatment and prevention costs. BRD is often referred to as the “bovine respiratory diseases complex” due to the multifactorial etiology.
The cost of death losses due to respiratory diseases vary around the world. Death losses in the U.S. are estimated to approach $1 billion annually. Losses in various European countries range from $75 to $120 million. Cattle with clinical or sub-clinical BRD do not gain weight or produce milk as well as healthy animals. Beef cattle with BRD gain less weight, have reduced feed efficiency and often produce a lower grade carcass at slaughter. Perino L. J., Apley M., Bovine Respiratory Disease, in CURRENT VETERINARY THERAPY 4 (FOOD ANIMAL PRACTICE), 4TH ED. 446-455 (Howard J. L., Smith R. A., eds., 1999). A direct correlation between pulmonary lesions observed at slaughter and reduced weight gains has been established in cattle with sub-clinical infections. Whittem T. E. et al., J. Am. Vet. Med. Assoc., 209:814-818 (1996).
In addition to the production losses associated with mortality and morbidity, significant costs are associated with the treatment of BRD due to the costs of various therapeutic agents and the labor required to administer these agents, along with the extra labor to isolate and observe these animals.
The pathogenesis of BRD is thought to be due to the interaction of environmental and physiological stresses coupled with infectious agents. Mannheimia (Pasteurella) haemolytica, Pasteurella multocida and Haemophilus somnus are considered part of the normal flora of the bovine upper respiratory tract. When environmental and physiological stress factors reduce the natural resistance and inhibit the pulmonary defense mechanisms these organisms proliferate and colonize the lower respiratory tract. In addition, various bovine viruses such as infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV) and parainfluenza 3 virus (PI-3) are known to have immunosuppressive effects in the lung.
Similarly, swine respiratory disease (SRD) also has a multifactional etiology. Bacterial infections caused by P. multocida, H. parasuis, Bordetella bronchiseptica, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis and Mycoplasma sp. can result in respiratory disease in swine, resulting in significant economic losses. Stresses such as crowding, mixing and moving of pigs and transient viral infections can contribute to the intensification of the disease.
These organisms can stimulate an excessive inflammatory process in the lungs by producing various toxins that stimulate the release of various cytokines, which up-regulate the inflammatory process. M. haemolytica, considered the most virulent of these organisms, also produces a leukotoxin that inhibits phagocytosis by leukocytes thus further enhancing its ability to colonize the lower respiratory tract. This process often results in a bacterial bronchopneumonia.
The pulmonary damage that results in death or morbidity is due to the excessive inflammatory response to the invading pathogens. Damage to host tissues occur as neutrophils, pulmonary alveolar macrophages and natural killer cells destroy infected cells. As cell membranes are damaged, arachidonic acid is released. Arachidonic acid is the substrate for the formation of various prostaglandins and other eicosanoids. The release of these biological active substances is critical to driving the inflammatory response that results in pulmonary lesions. Mosier D. A., Vet. Clin. North Am. Food Animal Prac., 13:483-493 (1997).
In general, therapy for BRD should be directed at achieving the following goals:
1. Controlling the infection—In animals where the infectious process is halted early, the need for repeat treatment is significantly reduced (see Apley M. D. & Fajt V. R., Vet. Clin. North Am. Food Anim. Prac., 14:291-313 (1998). The selection of the appropriate antimicrobial compound should be based on the antimicrobial sensitivity of the organism involved, the levels of the antimicrobial agent in the respiratory tract, ease of administration, the potential for injection site tissue damage and a dosing regime that minimizes the pain and stress associated with treatment.
2. Minimize the pulmonary damage—As the level of inflammation and subsequent pulmonary damage increases, the probability of repeat therapy increases and the rate of weight gain decreases. Lekeux P., Bovine Practitioner, 29:71-75 (1995); Scott P. R., J. Dairy Sci., 76(2):414-420 (1993).
3. Reduce pyrexia—Controlling the infection and reducing the inflammation will reduce the pyrexia (fever) thus increasing the potential for recovery. The feeling of well-being that accompanies the reduction of pyrexia may also improve the intake of nutrients by suppressing inappetence associated with disease and pyrexia.
For years antimicrobial therapy has been the mainstay of BRD therapy. There are many effective microbial agents currently available for the treatment of BRD. NUFLOR, an injectable formulation of the broad spectrum antibiotic florfenicol, has emerged as one of the leading antibiotics on a global basis. It is indicated for the treatment and control of BRD associated with M. haemolytica, P. multocida and H. somnus as well as for the prevention of respiratory disease in cattle at high risk of developing BRD associated with these bacteria. NUFLOR is also indicated for the treatment of bovine interdigital phlegmon (footrot, acute interdigital necrobacillosis, infectious pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. NUFLOR may be administered subcutaneously as well as intramuscularly.
The pathogenesis of BRD involves the development of a significant inflammatory process in the lungs and the subsequent development of pulmonary lesions, often leading to pulmonary consolidation. The degree of this inflammatory process can determine whether the disease results in mortality, a chronic “poor doer” or the animal recovers uneventfully. Various anti-inflammatory agents have been investigated regarding their ability to reduce the pyrexia, lung consolidation and weight loss associated with BRD.
The use of corticosteroids is generally contraindicated as ancillary therapy for BRD due to their ability to cause serious immunosuppression. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in conjunction with antibiotics, however, has been shown to be of benefit in the treatment of bovine respiratory disease. The nonsteroidal, anti-inflammatory agent flunixin meglumine has been demonstrated to be effective in rapidly reducing pyrexia associated with BRD. Flunixin has also been demonstrated to reduce pulmonary consolidation and the need for re-treatment with antibiotics.
Flunixin meglumine is the active ingredient in FINADYNE and BANAMINE (both available from Schering-Plough Animal Health Corporation, Union, N.J.). It has emerged as one of the leading NSAIDs for adjunctive therapy of BRD.
Flunixin meglumine has been studied extensively in regard to its use in conjunction with antibiotics for the treatment of BRD. While it is widely used for this indication, it has not been used in combination in the same formulation with florfenicol because the primary route of administration of flunixin is intravenous and florfenicol is administered intramuscularly or subcutaneously. Moreover, florfenicol formulations have been designed to provide prolonged blood levels of the antibiotic and flunixin would not be expected to have adequate bioavailability in such formulations. In addition, there have been concerns as to whether florfenicol and flunixin would be compatible in such formulations.
Flunixin meglumine has been used in conjunction with oxytetracycline, and products containing both flunixin meglumine and oxytetracycline are commercially available in Europe. However, such combination products require once per day administration for 3 to 5 days. Furthermore, resistance to the antibiotic oxytetracycline has become commonplace in regard to bacterial pathogens, including those commonly associated with BRD.
Accordingly, there is a need for conveniently administered, stable compositions that can control and prevent the infection and minimize the inflammation associated with bovine respiratory disease and other infectious diseases, while minimizing the pain and stress to the animal associated with treatment and the potential for injection site tissue damage.